The research in this proposal will apply genetic, cell biological and chemical screening approaches with the goal of identifying novel treatments for type 2 diabetes (T2D), thus addressing thematic areas 1 and 2 of this grants program. Due to a relative deficiency in pancreatic beta cells, T2D patients are unable to produce sufficient insulin to control their blood glucose levels. If the number of beta cells in T2D patients could be increased, their glycemic control could be significantly improved, thus delaying or preventing the devastating consequences of chronic hyperglycemia. It is well established that beta cells possess the capacity to dramatically increase their numbers by replication, suggesting the possibility of harnessing this replicative potential as a therapeutic avenue for T2D. However, genes that specifically control beta cell replication are largely unknown. Likewise, small molecules that can boost beta cell replication rates have not been described. To identify genes that control beta cell replication, we propose to use microarray analysis to compare the transcription profiles of actively replicating populations of beta cells to the profiles of quiescent populations. In this way, we will be able to identify candidate regulatory genes whose expression either positively or negatively correlates with replication status. In parallel, we will undertake a high-throughput small molecule screen on cultured pancreatic islets to identify compounds that can stimulate the rate of beta cell replication in vitro. Genes and compounds identified by these two analyses will then be tested in mouse models to determine their ability to regulate beta cell replication in vivo. Thus, the studies in this proposal are likely to lead to the identification of novel therapeutic targets and drug candidates for the treatment of diabetes. PUBLIC HEALTH RELEVANCE: The incidence of type 2 diabetes is rapidly increasing in the United States and worldwide. The negative impacts of long-term diabetes on a patient's health are significant, and carry with them a heavy financial burden. The therapies that will be developed as a result of the proposed research could be used to treat type 2 diabetes, and delay or prevent the devastating consequences of long-term disease. Thus, these therapies will both alleviate patient suffering while simultaneously reducing the financial costs of this disease.